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Endoglin: A New Target of Therapy for Heart Failure

内皮糖蛋白：心力衰竭治疗的新靶点

基本信息

批准号：
9295051
负责人：
Navin Kumar Kapur
金额：
$ 43.75万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295051
关键词：
ACVRL1 gene Activins Adult Affect Attenuated Biology Bone Morphogenetic Proteins Cardiac Cardiac Myocytes Cells Collagen Collagen Type I Complex Congestive Heart Failure Data Echocardiography Endoglin Endothelial Cells Endothelium Extracellular Matrix Failure Fibroblasts Fibrosis Glycoproteins Heart Heart failure Human Hypertrophy Hypoxia In Vitro Individual Knowledge Laboratories Laboratory Study Left Left Ventricular Function Ligand Binding Measures Mechanics Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Nature Pathway interactions Patients Phosphorylation Phosphotransferases Physiologic intraventricular pressure Physiology Population Pre-Clinical Model Proteins Public Health Receptor Signaling Regulation Reporting Research Personnel Role Signal Pathway Signal Transduction Specialist System TGFB1 gene Techniques Testing Tissues Transforming Growth Factor beta Transgenic Mice Transgenic Model United States National Institutes of Health Ventricular Wild Type Mouse base bone loss bone morphogenetic protein 9 coronary fibrosis cytokine design gain of function hemodynamics human tissue improved inhibitor/antagonist innovation insight loss of function mechanical properties mortality mouse model neutralizing antibody new therapeutic target novel novel strategies novel therapeutics patient population programs receptor receptor binding recombinant peptide response targeted treatment therapeutic development therapeutic evaluation

项目摘要

This new early stage investigator RO1 proposal explores new mechanisms regulating cardiac fibrosis, a major cause of morbidity and mortality for patients with heart failure (HF) Based on exciting new data generated with support from the NIH-KO8 program, we will explore a new mechanism for the role of endoglin, an auxiliary receptor for the pro-fibrogenic cytokine transforming growth factor beta (TGFb1), as a mediator of maladaptive cardiac remodeling. The PI is an advanced HF specialist, whose laboratory studies molecular mechanisms regulating TGFb1 and endoglin activity using preclinical models of HF and human tissue. The Kapur laboratory recently reported that endoglin facilitates TGFb1-mediated left and right ventricular (LV and RV) fibrosis, and further, that reduced endoglin expression improves survival in models of LV and RV failure. More recent data support that endoglin is required for signaling via bone morphogenetic protein 9 (BMP9) in endothelium, however a role for BMP9 in HF has not been explored. The current proposal applies expertise in endoglin biology, hemodynamics, and HF to the field of TGFb-mediated cardiac fibrosis, for which no specific therapy currently exists. This proposal tests the novel hypothesis that endoglin promotes cardiac fibrosis by negatively regulating BMP9, a new endogenous inhibitor of TGFb1-mediated collagen synthesis in cardiac fibroblasts, and further that reducing endoglin activity selectively increases BMP9 abundance, thereby limiting cardiac fibrosis and improving survival in HF. Preliminary data included in the proposal shows that 1) endoglin and BMP9 are highly expressed by non-myocyte cell populations in the heart, 2) endoglin negatively regulates BMP9 expression in human cardiac fibroblasts (hCF), 3) BMP9 inhibits TGFb1 mediated collagen synthesis in hCF, 4) loss of BMP9 promotes LV fibrosis after TAC, 5) reduced endoglin activity increases BMP9 abundance in the LV, and 6) neutralizing endoglin can reverse established cardiac fibrosis. Innovative aspects of the proposal include: (a) the use of hCF for in vitro studies, (b) transgenic mice developed specifically to study endoglin and BMP9 in HF, (c) pioneering techniques to study composition and mechanical properties of the extracellular matrix, and d) studies to test the translational potential of targeting endoglin and BMP9 activity in HF. To test this hypothesis three aims are proposed: (SA1) Determine the mechanisms underlying endoglin- dependent regulation of BMP9 signaling in hCF; (SA2) Determine the mechanisms underlying endoglin- dependent regulation of maladaptive remodeling in HF; (SA3) Test the utility of targeting endoglin/BMP9 activity to reverse established cardiac fibrosis in HF. This proposal explores a paradigm shifting hypothesis that has tremendous potential to impact our basic understanding of cardiac fibroblast physiology, TGFb superfamily signaling, and cardiac remodeling with important implications for the growing population of patients with HF.

这项新的早期研究者RO1提案探索了调节心脏纤维化的新机制